Ziprasidone is an antipsychotic agent that is chemically unrelated to phenothiazine or butyrophenone antipsychotic agents. Ziprasidone has the following chemical name 5-[2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinyl]ethyl]-6-chloro-1,3-dihydro-2H-indol-2- and structure:

Ziprasidone is administered to a host such as a mammal, preferably a human, for treatment of psychiatric disorders such as schizophrenia. Other uses for ziprasidone are disclosed in WO 03/070246, WO 01/91756, incorporated herein by reference. A process for preparation of ziprasidone HCl monohydrate having a mean particle size equal to or less than about 85 microns is also disclosed in U.S. Pat. No. 6,150,366 and EP 0 965 343 A2.
Ziprasidone has been marketed under the name GEODON as an oral capsule and as an injectable drug. GEODON capsules contain the monohydrate hydrochloride salt of ziprasidone, and come in 20, 40, 60 and 80 mg dosage forms. GEODON for injection contains a lyophilized form of ziprasidone mesylate trihydrate, and contains 20 mg base equivalent of ziprasidone.
A process for preparing Ziprasidone (“ZPR”) like compounds is disclosed in U.S. Pat. No. 4,831,031. In example 16 of the '031 patent, ziprasidone is prepared by nucleophilic reaction between 1,2-Benzisothiazole-3-piperazinyl (“BITP”) and 5-(2-chloroethyl)-6-chloro-1,3-dihydro-indole-2(2H)-one (“CEI”) in methyl-iso-butyl-ketone with Na2CO3 as a base and in the presence of a catalytic amount of sodium iodide (“NaI”). The yield provided is ˜20% after chromatography of the crude reaction product.
U.S. Pat. Nos. 5,206,366 and 5,338,846 disclose a process for preparing ziprasidone which react BITP free base or its hydrochloride salt with CEI in water in the absence of an organic solvent. In example 1 of the '846 patent, a solution of sodium carbonate in 5 volumes of water is mixed with CEI and BITP hydrochloride. The mixture is then stirred and heated to reflux for 13 hours and slurried at room temperature for 1 hour. The product is then subjected to subsequent work-up. The crude is purified by slurry in iso-propyl alcohol (“IPA”) and crystallized from tetrahydrofuran (“THF”). The yield is 83.8% (reaction+crystallization) and the purity of the crystallized solid is 99.7%.
In Example 1 of the '366 patent, ziprasidone is prepared from a reaction mixture of BITP free base in 5 volumes of water, sodium carbonate and CEI at 100° C. for 16 hours in the absence of an organic solvent. After approximately 16 hours of reflux, the reaction mixture is cooled to room temperature, stirred for approximately one hour and then filtered. The crude product obtained has a 91% yield and a purity of 94.5%.
In section entitled “experiment” of U.S. Pat. No. 5,312,925 (EP 05686191), a solution of carbonate in 5 volumes of water is mixed with BITP and CEI, and the resulting slurry is heated at reflux for 14 hours. The reaction mixture is then cooled and filtered. The wet product is then re-slurried in isopropyl alcohol at room temperature for 2 hours.
In page 35 of WO 03/070246 ziprasidone having a low des-chlorinated impurity content is prepared by reacting CEI with BITP in water in the presence of carbonate at reflux temperature for about one day. After cooling, the resulting solid is slurried in isopropanol and recrystallized from THF. The level of the impurity is controlled by purification of CEI before reaction.
WO 01/91756 discloses a derivative of ziprasidone which is called s-methyl-dihydro-ziprasidone. The only example provided uses dihydro-ziprasidone as starting material.
WO 00/59489 discloses metabolites of ziprasidone, particularly ziprasidone sulfoxide and ziprasidone sulfone. The examples provided in WO 00/59489 are in the present tense, i.e., prophetic. Ziprasidone is prepared in WO 00/59489 substantially as in U.S. Pat. No. 4,831,031. The sulfoxide and sulfone are then obtained from ziprasidone by oxidation with peroxide.
WO 00/72847 discloses a pharmaceutical composition of ziprasidone containing ziprasidone free base or a pharmaceutically acceptable ziprasidone acid addition salt, water, polysorbate, a viscosity agent, and colloidal silicon dioxide.
Reaction of BITP with CEI often results in impurities and low yields, including impurities resulting from BITP and CEI that is not consumed. Other than in water, a suitable organic solvent has been difficult to find for reaction of BITP with CEI. Form example, in U.S. Pat. No. 4,831,031, where MIK was used, only a 20% yield was obtained. There is a need in the art for organic solvents to carry the reaction between CEI and BITP.
Even with reactions that take place in water, repetition of these reactions leads to BITP not being consumed and being present as much as 10 times the level of CEI as area percentage HPLC. A disparity in the level of CEI to BITP remaining is problematic since the BITP remaining can no longer react if the CEI has been consumed. The BITP remaining becomes an impurity and results in a decrease in yield. There is a need in the art for additional processes for preparation of ziprasidone which increase the yield of the process and consume most of the BITP and CEI.